Epigenetic Regulation of Airway Epithelium Immune Functions in Asthma

Abstract

Asthma is a chronic inflammatory disease of the respiratory tract characterized by recurrent breathing problems resulting from airway obstruction and hyperresponsiveness. Human airway epithelium plays an important role in the initiation and control of the immune responses to different types of environmental factors contributing to asthma pathogenesis. Using pattern recognition receptors airway epithelium senses external stimuli, such as allergens, microbes, or pollutants, and subsequently secretes endogenous danger signaling molecules alarming and activating dendritic cells. Hence, airway epithelial cells not only mediate innate immune responses but also bridge them with adaptive immune responses involving T and B cells that play a crucial role in the pathogenesis of asthma. The effects of environmental factors on the development of asthma are mediated, at least in part, by epigenetic mechanisms. Those comprise classical epigenetics including DNA methylation and histone modifications affecting transcription, as well as microRNAs influencing translation. The common feature of such mechanisms is that they regulate gene expression without affecting the nucleotide sequence of the genomic DNA. Epigenetic mechanisms play a pivotal role in the regulation of different cell populations involved in asthma pathogenesis, with the remarkable example of T cells. Recently, however, there is increasing evidence that epigenetic mechanisms are also crucial for the regulation of airway epithelial cells, especially in the context of epigenetic transfer of environmental effects contributing to asthma pathogenesis. In this review, we summarize the accumulating evidence for this very important aspect of airway epithelial cell pathobiology.

Keywords: airway; allergy; asthma; epigenetic; epithelium; histone; methylation; microRNA (miRNA).

Figure 1

Schematic illustration of major epigenetic modifications. (A) Modification of histones such as histone acetylation/deacetylation via histone acetyltransferases (HATs)/histone deacetylases (HDAC) and methylation/demethylation via histone methyltransferases (HMT)/histone demethylases (HDM) can either activate or repress the target gene transcription. Histone acetylation is typically associated with higher expression of the gene. Histone methylation can be related to either higher or lower transcriptional activity, depending on the amino acid residue modified and the number of methyl groups added. (B) DNA methylation or demethylation of genomic DNA through DNA methyltransferases (DNMT) or ten-eleven translocation (TET) enzymes and others, respectively. Higher level of DNA methylation is typically associated with lower transcriptional activity of the respective gene. (C) MicroRNAs (miRNAs) and further small non-coding RNAs can interfere with gene expression through base pairing with messenger RNAs and thus inhibiting their translation into the encoded protein.

Figure 2

Overview of currently known key epigenetic modifications observed in lower airway epithelial cells from asthma/allergic airway inflammation conditions and—if known—associated functional consequences. The green color always indicates upregulation of the respective modification in asthmatics vs. healthy while red color identifies opposite regulation. EVs, extracellular vesicles; miRNA, microRNA; H3K18ac, histone H3K18 acetylation; H3K27me3, histone H3K27me3 trimethylation.